The field of pharmacogenetics is aimed at understanding how genetic variation contributes to variability in drug efficacy or toxicity. Agents in the thiazolidinedione (TZD) drug class, pioglitazone and rosiglitazone, are used commonly in the treatment of type 2 diabetes. Currently, it is unknown whether genetic variation influences TZD disposition (pharmacokinetics) and response (pharmacodynamics) in humans. Furthermore, few studies have evaluated whether genetics influences the magnitude of inhibitory drug-drug interactions in diabetes clinical pharmacology. The studies proposed within this application will focus on genetic variation within the cytochrome P450 2C8 (CYP2C8) metabolizing enzyme gene. CYP2C8 is responsible for the hepatic metabolism of TZDs. Polymorphisms within this gene decrease the activity of the metabolizing enzyme. The extent to which CYP2C8 polymorphisms influence TZD pharmacokinetics or pharmacodynamics in humans has not been fully elucidated. We will determine if genetic polymorphisms in the CYP2C8 gene contributes to variability in pioglitazone pharmacokinetics and pharmacodynamics in Caucasian and African American patients with type 2 diabetes. Like drug disposition and response, interindividual variability also exists in the magnitude of pharmacokinetic changes caused by inhibitory drug-drug interactions. Drug interactions are germane to diabetes pharmacotherapy because inhibition of drug metabolism may enhance the efficacy or toxicity of the hypoglycemic agent. The studies in this application will investigate gemfibrozil-mediated CYP2C8 inhibition of pioglitazone metabolism. We will determine if CYP2C8 polymorphisms affect the extent to which gemfibrozil alters pioglitazone metabolism and pharmacokinetics in humans. In doing so, we will target an important, but poorly defined area, of diabetes clinical pharmacology. The long term objective of this line of research is to more comprehensively characterize the contribution of genetics to interindividual variability in TZD disposition, response, and drug interactions. The goal of diabetes pharmacogenetic research is to better understand how a person's genetic make-up influences response to diabetes medications. In the future, this information may be used to aid in the selection of appropriate drug therapy for patients with type 2 diabetes.